Tamas Ördög
Laboratory for Neuroendocrinology
The University of Texas-Houston Medical School
Houston, TX 77225
Present Address:
Department of Physiology and Cell Biology
University of Nevada School of Medicine
Anderson 352
Reno, NV 89557-0046 tamas@scs.unr.edu

and

Ernst Knobil
Laboratory for Neuroendocrinology
The University of Texas-Houston Medical School
Houston, TX 77225

The concept of a neuronal signal generator in the central
nervous system that causes the rhythmic release of GnRH into
the pituitary portal circulation and the consequent pulsatile
secretion of the pituitary gonadotropic hormones was first proposed
nearly three decades ago. Since then, this notion has been verified
experimentally by the measurement of GnRH pulses coincident
with LH pulses in several species. In all mammals studied to
date, this "GnRH pulse generator" has been localized
to the arcuate region of the mediobasal hypothalamus. It is
an intrinsic property of this structure capable of functioning
without extrahypothalamic neural or humoral inputs. More recently,
its electrophysiological components have also been described.
These are rhythmic increases in multiunit electrical activity
(MUA "volleys") that are invariably synchronous with
the initiation of LH pulses. Analysis of single-unit components
of the multiunit signal has revealed that the MUA volleys represent
the increase in firing rate of individual units and not the
activation of previously quiescent cells.

The physiological significance of pulsatile GnRH secretion
was first demonstrated in female rhesus monkeys bearing bilateral
lesions in the mediobasal hypothalamus that abolished endogenous
GnRH production. In these animals, continuous GnRH infusion
failed to sustain gonadotropin secretion. Pulsatile administration
of GnRH at the physiological frequency of one pulse/in, however,
reestablished the pre-lesion levels of LH and FSH. These findings
have all been repeated in several other species including man
and have led to the development of various therapeutic applications.
More importantly, the pulsatile administration of GnRH at an
unvarying frequency of one pulse/in to such lesioned monkeys
with intact ovaries sustained entirely normal, 28-day ovulatory
menstrual cycles. Similar findings have been reported in women
deprived of endogenous GnRH secretion undergoing replacement
therapy with exogenous GnRH. These results also indicate that
the GnRH pulse generator plays but a permissive role in the
regulation of the female reproductive cycle, with peripheral
factors (notably the ovaries) being responsible for the timing
of the phases of the menstrual cycle ("pelvic clock").
Despite this, pulse generator frequency undergoes dramatic variations
throughout the menstrual cycle, mostly under the inhibitory
influence of gonadal steroids. In addition, a number of neurotransmitters
and neuropeptides modulate pulse generator activity. Some of
them mediate the actions of steroid hormones while others mediate
the inhibitory effects of environmental factors (e.g. "stress,"
severe excercise, caloric deprivation). GnRH pulse generator
activity is also arrested during pregnancy and lactation.

Intermittency of gonadotropin secretion is well conserved,
having been described in most vertebrates. Although recent in
vitro evidence suggests that the rhythmic signals may originate
from the GnRH cells themselves, the actual hypothalamic Zeitgeber
remains to be identified. This and the elucidation of the mechanisms
for pacemaking and integration of the component cells represent
the greatest challenges for the future.